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Journal: Brain research

167

Flavonoids have known anti-inflammatory and antioxidative actions, and they have been described as neuroprotective and able to reduce damage in CNS diseases. We evaluated the action of the flavonoid rutin in an animal model of focal cortical ischemia induced by unilateral thermocoagulation of superficial blood vessels of motor (M1) and somatosensory (S1) primary cortices. Ischemic rats were submitted to daily injections (i.p.) for five days, starting immediately after induction of ischemia. We tested two doses: 50mg/kg or 100mg/kg of body weight. Sensorimotor tests were used to evaluate functional recovery. Bioavailability in plasma was done by chromatographic analysis. The effect of treatment in lesion volume and neurodegeneration was evaluated 48h and 72h after ischemia, respectively. We observed significant sensorimotor recovery induced by rutin, and the dose of 50mg/kg had more pronounced effect. Thus, this dose was used in further analyses. Plasma availability of rutin was detected from 2h to at least 8h after ischemia. The treatment did not result in reduction of lesion volume but reduced the number of degenerated neurons at the periphery of the lesion. The results suggest rutin as an efficient drug to treat brain ischemia since it was able to promote significant recovery of sensorimotor loss, which was correlated to the reduction of neurodegeneration in the periphery of cortical injury. Increasing studies with rutin and other flavonoids might give support for further clinical trials with these drugs.

Concepts: Blood vessel, Stroke, Traumatic brain injury, Cerebral cortex, Ischemia, Flavonoid, Brain ischemia, Rutin

136

We used an umami substance, monosodium glutamate (MSG), as a simple stimulant to clarify the mechanism of the formation of emotional behavior. A 60 mM MSG solution was fed to spontaneously hypertensive rats (SHR), used as a model of attention-deficit hyperactivity disorder, from postnatal day 25 for 5 weeks kept in isolation. Emotional behaviors (anxiety and aggression) were then assessed by the open-field test, cylinder test and social interaction test. MSG ingestion during the developmental period resulted in a significant reduction in aggressive behavior but had few effects on anxiety-like behavior. Several experiments were performed to identify the reason for the reduced aggression with MSG intake. Blood pressure in the MSG-treated SHR was comparable to that of the controls during development. Argyrophil III staining to detect the very early phase of neuronal damage revealed no evidence of injury by MSG in aggression-related brain areas. Assessment of plasma amino acids revealed that glutamate levels remained constant (∼80 μM) with MSG ingestion, except for a transient increase after fasting (∼700 μM). However, lactate dehydrogenase assay in an in vitro blood-brain barrier model showed that cell toxicity was not induced by indirect MSG application even at 700 μM, confirming that MSG ingestion caused minimal neuronal damage. Finally, vagotomy at the sub-diaphragmatic level before MSG ingestion blocked its effect on aggressive behavior in the isolated SHR. The data suggest that MSG ingestion during the developmental period can reduce aggressive behavior in an attention deficit-hyperactivity disorder model rat, mediated by gut-brain interaction.

Concepts: Psychology, Amino acid, Educational psychology, Attention-deficit hyperactivity disorder, Hyperactivity, Glutamic acid, Monosodium glutamate, Umami

28

This fMRI study examined recall and familiarity for words and scenes using the novel recognition without cued recall (RWCR) paradigm. Subjects performed a cued recall task in which half of the test cues resembled studied items (and thus were familiar) and half did not. Subjects also judged the familiarity of the cue itself. RWCR is the finding that, among cues for which recall fails, subjects generally rate cues that resemble studied items as more familiar than cues that do not. For words, left and right hippocampal activity increased when recall succeeded relative to when it failed. When recall failed, right hippocampal activity was decreased for familiar relative to unfamiliar cues. In contrast, right Prc activity increased for familiar cues for which recall failed relative to both familiar cues for which recall succeeded and to unfamiliar cues. For scenes, left hippocampal activity increased when recall succeeded relative to when it failed but did not differentiate familiar from unfamiliar cues when recall failed. In contrast, right Prc activity increased for familiar relative to unfamiliar cues when recall failed. Category-specific cortical regions showed effects unique to their respective stimulus types: The visual word form area (VWFA) showed effects for recall vs. familiarity specific to words, and the parahippocampal place area (PPA) showed effects for recall vs. familiarity specific to scenes. In both cases, these effects were such that there was increased activity occurring during recall relative to when recall failed, and decreased activity occurring for familiar relative to unfamiliar cues when recall failed.

Concepts: Cerebral cortex, Cerebrum, Hippocampus, Limbic system, Entorhinal cortex, Relative direction, Perirhinal cortex, Parahippocampal gyrus

28

Myelin sheath, either in white matter or in other regions of brain, is vulnerable to ischemia. The specific events involved in the progression of ischemia in white matter have not yet been elucidated. The aim of this study was to determine histopathological alterations in cerebral white matter and levels of myelin basic protein (MBP) in ischemia-injured brain tissue during the acute and subacute phases of central nervous injury following whole-brain ischemia. The whole cerebral ischemia model (four-vessel occlusion (4-VO)) was established in adult Sprague-Dawley rats and MBP gene expression and protein levels in the brain tissue were measured using reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA) at 2 d, 4 d, 7 d, 14 d, and 28 d following ischemia. Demyelination was determined by Luxol fast blue myelin staining, routine histopathological staining, and electron microscopy in injured brain tissue. Results showed that edema, vascular dilation, focal necrosis, demyelination, adjacent reactive gliosis and inflammation occurred 7 d after ischemia in HE staining and recovered to control levels at 28 d. The absence of Luxol fast blue staining and vacuolation was clearly visible at 7 d, 14 d, and 28 d. Semiquantitative analysis showed that the transparency of myelin had decreased significantly by 7 d, 14 d, and 28 d. Demyelination and ultrastructual changes were detected 7 d after ischemia. The relative levels of MBP mRNA decreased 2 d after ischemia and this trend continued throughout the remaining four points in time. The MBP levels measured using ELISA also decreased significantly at 2 d and 4 d, but they recovered by 7 d and returned to control levels by 14 d. These results suggest that the impact of ischemia on cerebral white matter is time-sensitive and that different effects may follow different courses over time.

Concepts: Central nervous system, Nervous system, Neuron, ELISA, ELISPOT, Cerebellum, Myelin, Myelin basic protein

28

BACKGROUND: Exposing the brain to a sub-damaging stimulus can protect against a subsequent lethal insult, a phenomenon termed preconditioning. The aim of this study was to investigate the neuroprotective effect of low dose LPS (lipopolysaccharide) pretreatment in endotoxin induced periventricular leukomalacia (PVL) in a rat model. Methods: Wistar rats with dated pregnancies were allocated to 5 groups: (i) no LPS administered, intraperitoneally (i.p.) pyrogen-free saline injected (Control group), (ii) 500μg/kg LPS administrated i.p. on days 18 and 19 (PVL group), (iii) 50μg/kg LPS administrated i.p. on day 17 followed by 500μg/kg LPS i.p. on days 18 and 19 (PC-PVL group), (iv) 50μg/kg LPS administrated on day 17 (PC only), and (v) i.p. pyrogen-free saline injected control group on day 17. Results: LPS-preconditioning given 24h before potent LPS exposure significantly reduced the number of apoptotic cell deaths and prevented hypomyelination. Antioxidant enzyme gene expression levels (Superoxide Dismutase-SOD1, SOD2, and SOD3) were increased and Tumor Necrosis Factor (TNF)α expression levels were decreased in the PC+PVL group when compared with the PVL group. Conclusion: Low-dose LPS given one day before potent doses of LPS reduces antepartum LPS-induced brain damage. The mechanisms of protection might involve oxidation and inflammation.

Concepts: Gene, Gene expression, Organism, Superoxide dismutase, Lipopolysaccharide, Tumor necrosis factor-alpha, Periventricular leukomalacia, Spastic diplegia

28

Cofilin is the major actin-depolymerizing factor in the CNS for the regulation of actin dynamics. Neurodegenerative stimuli can induce the formation of cofilin rod, a pathological structure composed of cofilin and actin. The formation of cofilin rod was found to disrupt synapse function and cause neurite loss. The aim of the present study is to study the whole process of cofilin rod formation pattern in cultured hippocampal neurons under excitotoxic stimulation and to explore its underlying pharmacological mechanism. By using live cell imaging of neurons overexpressing EGFP-tagged wild type cofilin, we found a two-phase pattern of rod formation induced by glutamate stimulation. The early phase of rod formation occurred shortly after stimulation (∼0.5h) but quickly dissolved within 2h. The second phase happened within a much longer time window, 8h after stimulation. Immunostaining of endogenous cofilin in neurons also confirmed this glutamate stimulation induced two-phase rod formation pattern. The first phase was co-related with intracellular calcium concentration and pH increase while the second phase was not. These two phases of cofilin rod formation induced by glutamate stimulation was antagonized by both non-NMDA and NMDA receptor antagonist DNQX and AP5, respectively. Our results for the first time demonstrate the dynamic cofilin rod formation pattern under stress stimulation in detail by time lapse imaging. These findings reveal a novel time course of excitotoxicity induced neuronal damage and indicate a potential target of neuropathy treatment of neurodegenerative diseases.

Concepts: Nervous system, Neuron, Receptor, Hippocampus, Ligand, Receptor antagonist, NMDA receptor, Excitotoxicity

28

Adults of three age groups (18-27, 39-45, and 59-66 years) performed an auditory duration discrimination task with short (200ms) or long (400ms) sinusoidal tones. Performance was highly accurate and reaction times were on the same level in all groups, indicating no differences in auditory duration processing. Task irrelevant rare changes of the frequency of the stimuli were introduced to check whether the subjects, firstly, were distracted by changes in the environment while focusing on the task relevant information (indicated by prolonged responses), and, secondly, could re-focus on the relevant task after distraction. The results show that a distraction effect is present in all groups. Importantly, the 59-66 years group showed a behavioral distraction effect nearly twice as high as the other groups. The event-related brain potentials (ERPs) show mismatch negativity (MMN), P3a, and reorienting negativity (RON) elicited by deviants which are present in all groups. Aging effects on these ERP components were observable in all three components but a revealed a weak significant effect for the MMN only. Taken together, the behavioral and ERP results suggest that the function of balancing the processing of task irrelevant changes in the stimulation while focusing on task relevant information is effective during adulthood until the 7(th) decade of life.

Concepts: Effect, Effectiveness, Ageing, Human behavior, Potential, Event-related potential, Distraction, Attention span

27

Previous studies have indicated involvement of the mitogen-activated protein kinase (MAPK) pathway in heterosexual interactions among rats. Very few studies, however, have focused its role in isosexual social interactions. We studied the male rat’s isosexual social interactional behavior using (i) the three-chambered social interaction box and (ii) phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2) to localize the brain regions that are activated during isosexual behavior. When faced with the social target side of the box versus the inanimate side, all rats preferred the social target side. Within 10min, isosexual social interactions induced a rapid increase in pERK1/2 expression in the brain, especially the main olfactory epithelial (MOE)-related brain regions. After ZnSO4-induced olfactory deprivation, rats showed no preference for either the social target or inanimate side, with a concomitant decrease in pERK1/2 expression in MOE-related brain regions. Additionally, to determine the role of pERK1/2 in isosexual social interactional behavior, rats were injected intraperitoneally with SL327 (30mg/kg, a MAPK kinase inhibitor). Although SL327 dramatically down-regulated expression of brain pERK1/2, experimental animals also spent significantly more time in the social target side. These results indicate that (i) A brief interacting with a male partner induced rapidly phosphorylated ERK1/2 in the rat’s brain. (ii) Destroy the function of MOE abolished the rats' isosexual social interactional behavior. (iii) Suppressed the phosphorylated ERK1/2 in the rats' brain disrupt their normal social behaviour.

Concepts: Signal transduction, Interaction, Sociology, MAPK/ERK pathway, Behavior, Mitogen-activated protein kinase, Extracellular signal-regulated kinases, Social relation

27

Excessive activation of AMPA receptor has been implicated in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). However, it is not clear why motor neurons are preferentially sensitive to AMPA receptor mediated excessive [Ca(2+)]i rise and excitotoxicity. In the present study we examined whether palmitoylation regulates Ca(2+) permeability of AMPA receptor and excitotoxicity in cultured spinal cord neurons. We adapted chronic 2-bromopalmitate (2-BrP) treatment to achieve depalmitoylation and examined its effect on the cytotoxicity in spinal cord neurons exposed to AMPA. The change in AMPA induced signaling and cytotoxicity in motor neurons and other spinal neurons under identical conditions of exposure to AMPA was studied. 2-BrP treatment inhibited AMPA induced rise in [Ca(2+)]i and cytotoxicity in both types of neurons but the degree of inhibition was significantly higher in motor neurons as compared to other spinal neurons. The AMPA induced [Na(+)]i rise was moderately affected in both type of neurons on depalmitoylation. Depalmitoylation reduced the expression levels of AMPA receptor subunits (GluR1 and GluR2) and also PSD-95 but stargazin levels remained unaffected. Our results demonstrate that 2-BrP attenuates AMPA receptor activated Ca(2+) signalling and cytotoxicity preferentially in motor neurons and suggest that AMPA receptor modulation by depalmitoylation could play a significant role in preventing motor neuron degeneration.

Concepts: Neuron, Spinal cord, Amyotrophic lateral sclerosis, Excitotoxicity, Neuromuscular junction, Motor neuron, Motor neurone disease, Motor nerve

27

High frequency stimulation (HFS) applied in the brain has been shown to be efficient for treating several brain disorders, such as Parkinson’s disease and epilepsy. But the mechanisms underlying HFS are not clear. In particular, the effect of HFS on axons has been intriguing since axonal propagation plays an important role in the functional outcome of HFS. In order to study the potential effect of axonal block by HFS in-vivo, both orthodromic- and antidromic-HFS (O-HFS, A-HFS) with biphasic pulses were applied to the hippocampal CA1 region in anaesthetized rats. Changes in the amplitude and latency of orthodromic- and antidromic-population spikes within 1-min long period of stimulation at 50, 100 and 200Hz HFS were analyzed. The results show that except for a short onset period, activity evoked by O-HFS with a frequency over 100Hz could not be sustained. For A-HFS at frequencies over 100Hz, the amplitudes and the latencies of antidromic population spike (APS) greatly decreased and increased respectively. Significantly larger changes in APS latency were observed in HFS than those generated at low frequency, suggesting a suppression of axon conduction by HFS. Furthermore, the CA1 somata remained excitable while failing to respond to excitation from orthodromic or antidromic HFS. Taken together, these results show that HFS produces an axonal block of both afferent and efferent fibers localized to the area of stimulation since it does not affect the excitability of CA1 somata. This effect of HFS on axons causes a functional disconnection of axonal pathways that is reversible and temporary. The reversible disconnection or temporary deafferentation between putative therapeutic targets could have extensive implication for various clinical applications of HFS to treat brain diseases.

Concepts: Nervous system, Neuron, Neuroanatomy, Brain, Cerebral cortex, Neurology, Hippocampus, Axon